Abstract
Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Androgen Antagonists / chemical synthesis
-
Androgen Antagonists / chemistry*
-
Androgen Antagonists / metabolism
-
Androgen Receptor Antagonists / chemical synthesis
-
Androgen Receptor Antagonists / chemistry*
-
Androgen Receptor Antagonists / metabolism
-
Androgen Receptor Antagonists / pharmacology
-
Androgens / chemistry*
-
Androgens / pharmacology
-
Crystallography, X-Ray
-
Drug Design
-
Drug Resistance, Neoplasm / genetics*
-
Humans
-
Male
-
Molecular Structure
-
Molecular Targeted Therapy
-
Prostatic Neoplasms / drug therapy
-
Prostatic Neoplasms / genetics*
-
Protein Binding
-
Receptors, Androgen / chemistry
-
Receptors, Androgen / metabolism*
-
Structure-Activity Relationship
Substances
-
Androgen Antagonists
-
Androgen Receptor Antagonists
-
Androgens
-
Receptors, Androgen